Thursday, January 26, 2017

Hepatitis C Virus Genotype 4: Genotype 1's Little Brother

2017 Jan;24(1):4-12. doi: 10.1111/jvh.12620. Epub 2016 Dec 1.

Hepatitis C Virus Genotype 4: Genotype 1's Little Brother
J. Llaneras; M. Riveiro-Barciela; M. Buti; R. Esteban

Chronic hepatitis C virus (HCV) infection affects approximately 130-150 million individuals worldwide.[1] Twenty per cent of chronic HCV infections are caused by HCV genotype 4 (GT4).[2] Infection by this genotype is more common (and highly prevalent), in the Middle East and Africa, where GT4 is responsible for more than 80% of HCV infections. In some Mediterranean European countries, especially Italy, France, Greece and Spain, the prevalence of GT4 has increased, accounting for 10%-20% of HCV infections. This genotype is usually seen in intravenous drugs users, HCV/HIV co-infected patients and immigrants from Africa or the Middle East.[3, 4] The prevalence of this infection in the United States is estimated at around 1%.[5]

In the last 5 years, HCV treatment has undergone a major change due to emergence of the new direct-acting antiviral (DAA) agents. Various therapeutic strategies have been designed to treat several HCV genotypes with these drugs.

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recently approved several drugs for the treatment of chronic HCV GT4 infection. The classical therapies for GT4, such as pegylated alpha interferon 2a or 2b (PegIFN) and ribavirin (RBV), are giving way to the new DAA agents. The following combinations have been approved for GT4 therapy: sofosbuvir (SOF), an NS5B polymerase inhibitor[6] plus ribavirin; sofosbuvir plus simeprevir (SMV), an NS3/4A protease inhibitor[7]; sofosbuvir plus daclatasvir (DCV), an NS5A protease inhibitor[8]; ombitasvir (OBV), an NS5A protein inhibitor, plus paritaprevir, another NS3/4A protease inhibitor, boosted with ritonavir (PTV/r)[9]; the fixed-dose combination of sofosbuvir with ledipasvir (LDV), an NS5A protease inhibitor[10]; the fixed-dose combination of elbasvir (EBR), an NS5A inhibitor, and grazoprevir (GZR), an NS3/4A protease inhibitor[11]; and sofosbuvir with velpatasvir (VEL), an NS5A protein inhibitor.[12]

As compared with HCV genotype 1 (GT1), few trials have been performed in GT4 patients, and the samples studied are smaller. All the various DAA combinations have demonstrated effectiveness and safety in the treatment of patients with GT4 infection. However, the AASLD and EASL guidelines do not recommended them all, and rating of the evidence differs because of the type of studies performed, the safety profiles reported, drug–drug interactions, the availability across different countries and the cost of treatment.[13, 14] As in other HCV genotypes, the new DAA agents have led to improvements in the efficacy and safety of treatment in GT4 and have displaced PegIFN combined therapies to a secondary position (Tables 1 and 2).

Table 1. EASL recommended therapies for chronic HCV gentoype 4[13]
RecommendationRegimen and daily dosingDuration (weeks)
  1. DCV, daclatasvir; LDV, ledipasvir; OBV, ombitasvir; PTR/r, paritaprevir/ritonavir; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir.
  2. a Patients with compensated cirrhosis with contraindications to the use of ribavirin on treatment should receive the fixed-dose combination of sofosbuvir and ledipasvir for 24 weeks without ribavirin.
IFN-free regimens in treatment-naive patients with or without cirrhosis
A1LDV/SOF (90 mg/400 mg)12
A1SOF/VEL (400 mg/100 mg)12
A1OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV12
A1EBR/GZR (50 mg/100 mg)12
A1SOF + SMV (400 mg/150 mg)12
B2SOF + DCV (400 mg/60 mg)12
IFN-free regimens in treatment-experienced patients with or without cirrhosis
B1LDV/SOF (90 mg/400 mg) + weight-based RBV12a
A1SOF/VEL (400 mg/100 mg)12
A1OBV/PTV/r (25 mg/150 mg/100 mg) + weight-based RBV24
B1SOF + SMV (400 mg/150 mg) + weight-based RBV12a
B2SOF + DCV (400 mg/60 mg) + weight-based12a

Table 2. American Association for the Study of Liver Diseases (AASLD) recommended therapies for chronic hepatitis C virus (HCV) genotype 4

RecommendationRegimen and daily dosingDuration (weeks)
  1. a Patients with prior on-treatment virological failure should be treated with 16 weeks and adding weight-based ribavirin.
Treatment-naive or treatment-experienced with or without cirrhosis recommended regimens[14]
A1OBV/PTV/r (25/150/100 mg) + weight-based RBV12
A1SOF/VEL (400/100 mg)12
B2EBR/GZR (50/100 mg)12a
B2LDV/SOF (90/400 mg)12
This article reviews the currently available data and the new treatments under development for patients with chronic HCV GT4 infection.

2 Historical Situation
2.1 Interferon-based therapies
Four IFN-based therapies have been approved by the FDA and the European Medicines Agency (EMA). Currently, none of them are recommended by the American Association for the Study of Liver Diseases (AASLD) or the European Association for the Study of the Liver (EASL) guidelines because of the superiority of IFN-free therapies in terms of efficacy and safety.

2.1.1 Pegylated interferon plus ribavirin
The first treatment for GT4 patients was PegINF plus ribavirin (RBV), which provided a sustained virological response (SVR) rate of around 45% in treatment-naive patients receiving pegylated alpha interferon (2a or 2b) plus RBV for 24-48 weeks.[15-17] In a large real-world cohort study, PROPHESYS, 317 patients with chronic HCV GT4 infection received this regimen.[18] The overall SVR24 rate (sustained virological response at week 24) was 41%, with a lower value (27%) in patients with cirrhosis. The limitations of this therapy are the lengthy duration, adverse events associated with PegINF, and low applicability in patients with advanced liver disease.

2.1.2 Sofosbuvir plus pegylated interferon plus ribavirin
Sofosbuvir is a potent nucleotide analogue inhibitor of the HCV NS5B polymerase with activity against all HCV genotypes.[6] SOF plus PegINF and RBV for 12 weeks was evaluated in the NEUTRINO trial,[19] a phase-III study that included 28 patients infected by HCV GT4. SVR12 (sustained virological response at week 12) was achieved in 27 of the 28 patients (96%). The limitation of this regimen is that it is PegIFN-based, with all that this implies.

2.1.3 Simeprevir plus pegylated interferon plus ribavirin
Simeprevir, an NS3/4 inhibitor, is active against genotypes 1, 2 and 4.[7] The RESTORE study evaluated the efficacy and safety of SMV plus PegIFN plus RBV for 12 weeks followed by PegIFN and RBV for an additional period of 12 or 36 weeks in 107 patients HCV infected with GT4, including treatment-naïve and treatment-experienced patients.[20] Overall, 65.4% (70/107) of patients achieved SVR12, with a lower rate in treatment-experienced patients.

2.1.4 Daclatasvir plus pegylated interferon plus ribavirin
Daclatasvir is an NS5A inhibitor with activity against all HCV genotypes.[8] In the phase-III COMMAND-4 study, 124 GT4 patients were randomized to receive DCV plus PegIFN plus RBV for 24-48 weeks or PegIFN plus RBV for 48 weeks.[21] SVR12 rates were 82% (67/82) with DCV plus PegIFN plus RBV vs 43% (18/42) with PegIFN plus RBV.
Although SVR12 rates are higher in DAA plus PegIFN regimens than in PegIFN plus RBV, DAA plus PegIFN regimens do not achieve higher SVR12 rates than the currently available IFN-free combinations, which have the additional advantages of a shorter treatment duration and fewer adverse events.

3 Interferon-Free Therapies
Direct-acting antiviral agents have brought about a revolution in the efficacy and safety of HCV treatment and have enabled treatment of more complex cases: patients with advanced liver disease or decompensated disease, those with IFN contraindications or intolerance and those unwilling to receive IFN treatment.

Among IFN-free therapies, four combinations are recommended in the new, updated AASLD guidelines[14] for treating naïve and experienced patients (with or without cirrhosis): two NS5B inhibitor plus NS5A inhibitor combinations, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir; and two NS5A inhibitor plus NS3/4 inhibitor combinations, ombitasvir/paritaprevir/ritonavir (with RBV) and elbasvir/grazoprevir. In most cases, all these combinations are used in 12-week regimens (Table 3).

Table 3. Interferon-free combination regimens with new DAA agents with activity in GT4

  1. a Fixed-dose combination.
Paritaprevir/r Ombitasvira
Grazoprevir Elbasvira

3.1 NS5B inhibitor plus NS5A inhibitor
3.1.1 Sofosbuvir/ledipasvir
The NIAID SYNERGY study, a phase-IIA trial, evaluated the combination of SOF/LDV in a cohort of 21 HCV GT4-infected patients.[22] The regimen was SOF 400 mg combined with LDV 90 mg in one pill, once daily for 12 weeks. The cohort included 13 (62%) treatment-naïve patients and eight (38%) treatment-experienced patients; three patients had moderate–severe liver fibrosis (F3 in 2 and F4 in 1). Twenty (95%) patients achieved SVR12 (100% in the protocol analysis). One patient did not complete the 12-week treatment regimen because of nonadherence. There were no treatment discontinuations due to adverse events. The most common side effects were diarrhoea, fatigue, nausea and upper respiratory tract infection. This controlled study showed that this one-pill once-daily treatment was highly effective and safe in GT4-infected patients. Further studies are needed to expand the recommendations for difficult-to-treat patients with GT4 infection.

Abergel et al.[23] evaluated SOF/LDV for 12 weeks in 44 patients infected by HCV GT4, including 10 (23%) with cirrhosis and 22 (50%) who were treatment-experienced. The overall SVR12 rate was 93%. As to NS5A resistance-associated substitutions (RASs), 22 of 27 (89%) patients with NS5A RASs and all those without RASs achieved SVR12. L30R was the most prevalent NS5A resistant-associated substitution (RAS) in the cohort. NS5B RASs were not detected at baseline. Three patients relapsed within the first 4 weeks after completion of treatment. Two were treatment-experienced, and none had cirrhosis. The most common side effects were similar to those seen in other cohorts (asthenia, headache and fatigue).

3.1.2 Sofosbuvir/velpatasvir
Velpatasvir is a pangenotypic HCV NS5A inhibitor with antiviral activity against genotypes 1-6. The EMA and FDA have authorized use of the SOF 400 mg plus VEL 100 mg fixed combination in one pill daily.[12]

Sofosbuvir/velpatasvir was evaluated in ASTRAL-1, a phase-III study that enrolled 624 patients with HCV infection, including some cirrhotic and treatment-experienced patients.[24] Patients previously treated with DAA agents were excluded. Overall, 116 (19%) patients had genotype 4 infection, 121 (19%) had cirrhosis, and 423 (68%) were treatment-naïve. All patients received a 12-week regimen of SOF/VEL. SVR12 rates were 100% (116/116) in GT4-infected patients, regardless of their fibrosis status or whether they had previously received treatment. At baseline, 50 GT4-infected patients had NS5A RASs, but all achieved SVR12. No significant differences were observed in adverse event rates between the SOF/VEL regimen and placebo. The most frequent adverse effects were headache, fatigue and nasopharyngitis.

Although the GT4-infected sample size was small, this 12-week combination regimen was easy to comply with, highly effective, and safe, even in those with advanced liver fibrosis and treatment-experienced patients.

3.2 NS5A inhibitor plus NS3/4 inhibitor
3.2.1 Ombitasvir/paritaprevir/ritonavir
Ombitasvir is a NS5A inhibitor and paritaprevir a NS3/4A protease inhibitor that is coadministered with low-dose ritonavir to increase paritaprevir serum levels.[9] This combination was analysed in the multicentre phase-IIb, PEARL-I study[25] including 135 noncirrhotic GT4 patients, 86 (63.7%) of whom were treatment-naïve. Treatment-experienced patients had failed PegINF plus RBV. Treatment-naïve patients were randomly assigned to a 12-week regimen of OBV plus PTV/r with or without weight-based RBV. All treatment-experienced patients received a 12-week regimen of OBV plus PTV/r with weight-based RBV. In treatment-naïve patients, SVR12 rates were 100% (42/42) in the RBV-containing regimen and 91% (40/44) in the RBV-free regimen, with no significant differences. All treatment-experienced patients achieved SVR12 (49/49). Two patients in the treatment-naïve group with an RBV-free regimen prematurely discontinued treatment: one was lost to follow-up and the other experienced viral breakthrough at week 8 of treatment. Two other patients in the same group relapsed within 12 weeks post-treatment. All were subtype GT4d, and all had RASs at the time of failure that were not present at baseline. The predominant NS3 RAS was D168V, and the NS5A RASs were L28S or L28V. The regimen was found to be safe. The most common adverse effect was headache, but there were no adverse event-related discontinuations or dose interruptions.
The efficacy and safety of this regimen in cirrhotic patients was evaluated in the multicentre, phase-III AGATE-I study,[26] including HCV GT4-infected treatment-naïve or treatment-experienced patients with compensated cirrhosis. Patients were randomized into two arms; one received a 12-week regimen of OBV plus PTV/R with weight-based RBV once daily and the other a 16-week regimen with the same combination. Preliminary results showed SVR12 rates of 97% (57/59) in patients with the 12-week regimen vs 98% (60/61) with the 16-week regimen. One patient receiving the 12-week regimen who did not achieve SVR12 had discontinued treatment on day 1. The other was a man with HCV subtype GT4a and a previous null response to PegINF plus RBV. At baseline, he had the P58L NS5A RAS and no NS3 RASs. At failure, he showed newly emergent NS5A RASs: L28M and Y93H. Thirty-six patients in the AGATE-I cohort had RASs at baseline, and all but one achieved SVR12. In the 16-week regimen arm, SVR12 results could not be reported for one patient because of missing data. This combination was well tolerated, with no discontinuations due to adverse events. The most important events recorded were asthenia, fatigue, headache and anaemia, which were more common in the lengthier, 16-week arm.

AGATE-II is a phase-III trial carried out in Egypt, evaluating OBV plus PTV/r with RBV for GT4-infected patients, including those with compensated cirrhosis.[27] In total, 160 patients were enrolled, 100 noncirrhotic and 60 compensated cirrhotic patients. Half were treatment-experienced (61% prior null responders, 24% prior relapsers and 15% partial responders). Noncirrhotic patients received co-formulated OBV plus PTV/R once daily plus weight-based RBV for 12 weeks. Patients with compensated cirrhosis were randomized into two arms with the same regimen for 12 weeks and 24 weeks, respectively. SVR12 rates were high 94% (94/100) in the noncirrhotic arm: one patient failed while on treatment, one discontinued by withdrawing consent, data were missing in another, and three patients relapsed. SVR12 in the 12-week cirrhotic arm was 97% (30/31), with a single patient failing on treatment, and SVR12 in the 24-week arm was 96% (27/29), with missing data in one patient during follow-up and one on-treatment failure. The most common adverse events were fatigue (12%) and headache (15%). Extension of therapy to 24 weeks did not provide any additional benefits in cirrhotic patients, and there were more adverse events and a higher haemoglobin decrease in this arm.

3.2.2 Elbasvir plus grazoprevir
Elbasvir is an NS5A inhibitor, active against genotypes 1, 2a, 3, 4, 5 and 6. Grazoprevir is an NS3/4 protease inhibitor that is active against HCV genotypes 1, 2, 4, 5 and 6.[11]
The C-EDGE treatment-naïve study was an international, randomized, blinded, placebo-controlled trial investigating the combination of EBR 50 mg plus GZR 100 mg in one daily pill for 12 weeks in treatment-naive cirrhotic and noncirrhotic patients with chronic HCV genotype 1, genotype 4 and genotype 6 infection.[28] The overall SVR12 rate for all genotypes was 95%. SVR12 in GT4 treatment-naive patients was 100% (18/18). RASs were analysed in GT4 patients at baseline. NS3 RASs were present in seven of 18 (39%) patients, NS5A RASs in nine of 18 (50%) patients, and both RASs (NS5A and NS3) were found in two patients. In this study, the presence of RASs did not have an impact on SVR12 in GT4 patients. The most common adverse events in the cohort were headache (17%), fatigue (16%) and nausea (9%).

The C-EDGE treatment-experienced study evaluated the efficacy of a 12-week or 16-week regimen in HCV-infected patients who had failed PegIFN treatment. Patients received a one-pill regimen of EBR plus GZR with or without weight-based RBV.[29] SVR12 rates in GT4 patients receiving the 12-week regimen without or with RBV were 78% (7/9) and 93% (14/15), respectively. SVR12 rates in those receiving the 16-week regimen without or with RBV were 60% (3/5) and 100% (8/8), respectively. Baseline RASs and subgenotypes did not seem to have an impact on SVR12 rates.
Asselah et al.[30] reported data from phase-II and phase-III studies including a total of 103 GT4-infected patients treated with EBR/GZR. Sixty-six treatment-naïve patients were enrolled to receive EBR/GZR for 12 weeks and another 10 patients received the same regimen plus weight-based RBV for 12 weeks. Ninety-six (54/56) patients achieved SVR12 in the RBV-free regimen, one patient was lost to follow-up, and other relapsed. In the RBV regimen, SVR12 rates were 100% (10/10). Treatment-experienced patients were divided into four arms, 12 weeks or 16 weeks of treatment with or without weight-based RBV. SVR12 rates were higher in the 16-week regimens and RBV-associated regimens than in the 12-week regimens or RBV-free regimens. Two patients in the 12-week regimen relapsed, one in the RBV-associated regimen and the other in the RBV-free regimen. The other two patients failed on treatment in the 16-week regimen without RBV. All treatment-naive patients who had NS5A RASs at baseline achieved SVR12. In total, 81% (13/16) of treatment-experienced patients who achieved SVR12 had NS5A RASs at baseline, and 100% of treatment-experienced patients with NS3 RASs at baseline achieved SVR12.

The 12-week regimen without RBV is an attractive combination for treatment-naïve patients and PegIFN relapsers, including patients with compensated cirrhosis. In treatment-failed patients, 16-week therapy duration is associated with a higher SVR12 (Table 4).

Table 4. (a) SVR12 in GT4 hepatitis C virus (HCV)-infected patients without liver cirrhosis treated with IFN-free regimens. (b) SVR12 in GT4 HCV-infected patients with liver cirrhosis treated with IFN-free regimens. (c) SVR12 in GT4 HCV-infected patients with and without liver cirrhosis treated with IFN-free regimens
Treatment regimenDuration (weeks)NoPrior HCV treatmentSVR12 rate % (no SVR/total)Virological failures (no of cases)
  1. EBR, elbasvir; GZR, grazoprevir; LDV, ledipasvir; OBV, ombitasvir; PTR/R, paritaprevir/ritonavir; RBV, ribavirin; SOF, sofosbuvir; TE, treatment-experienced patients; TN, treatment-naive patients; VEL, velpatasvir.
  2. a Regimen without ribavirin.
  3. b Regimen with ribavirin.
(a) NS5B/NS5A
SOF/VEL (ASTRAL-1)[24]1289Treatment-experienced Treatment-naive100% (89/89)
SOF/LDV (NIAID SYNERGY)[22]1214Treatment-experienced Treatment-naive93% (13/14)
SOF/LDV Abergel et al.[23]1234Treatment-experienced Treatment-naive91% (31/34)Relapsers: 3
OBV/PTV/r (PEARL-1)[25]12135Treatment-experienced Treatment-naive91% (40/44) TNaVirological breakthrough: 1 Relapsers: 2
100% (42/42) TNb
100% (49/49) TEb
OBV/PTV/r + RBV (AGATE-II)[27]12100Treatment-experienced Treatment-naive94% (94/100)Breakthrough: 1 Relapsers: 3
(b) NS5B/NS5A
SOF/VEL (ASTRAL-1)[24]1227Treatment-experienced Treatment-naive100% (27/27)
SOF/LDV (NIAID SYNERGY)[22]127Treatment-experienced Treatment-naive100% (7/7)
SOF/LDV Abergel et al.[23]1210Treatment-experienced Treatment-naive100% (10/10)
OBV/PTV/r + RBV (AGATE-I)[26]12
97% (57/59) 12 weeks
98% (60/61) 16 weeks
Virological breakthrough: 1
OBV/PTV/r + RBV (AGATE-II)[27]12
97% (30/31) 12 weeks
96% (27/29) 24 weeks
Virological breakthrough: 2
(c) NS5A/NS3/4
GZR/EBR (C-EDGE TN)[28]1218Treatment-naive100% (18/18)
37Treatment-experienced78% (7/9) 12 weeksa
93% (14/15) 12 weeksb
60% (3/5) 16 weeksa
100% (8/8) 16 weeksb
GZR/EBR Asselah et al.[30]12
103Treatment-experienced Treatment-naiveTN
96% (54/56) 12 weeksa
100% (10/10) 12 weeksb
78% (7/9) 12 weeksa
93% (14/15) 12 weeksb
66% (3/5) 16 weeksa
100% (8/8) 16 weeksb
Relapsers: 3 Virological breakthrough: 2

3.3 Other interferon-free regimens accepted for treating HCV GT4 infection
3.3.1 Sofosbuvir plus ribavirin
Sofosbuvir plus RBV was the first IFN-free therapy used for GT4 infection, but it is no longer recommended. In a phase-II study, 60 patients of Egyptian ancestry with chronic HCV GT4 infection received a combination of SOF plus RBV.[31] Half of the patients had been previously treated. Patients were randomly allotted 1:1 to receive SOF 400 mg and weight-based RBV in both groups, but with treatment durations of either 12 or 24 weeks. SVR12 was achieved in 68% of patients in the 12-week group and 93% in the 24-week group. The most common adverse events were headache, insomnia and fatigue. A larger number of adverse events were reported in the 24-week group due to the longer treatment duration. This study had a limited sample, and it included only a few difficult-to-treat patients.

Another trial carried out in Egypt analysed the efficacy and safety of the same combination in 103 patients,[32] 52% treatment-experienced and 17% with cirrhosis at baseline. Patients were randomly assigned to one of two arms: SOF 400 mg and a weight-based daily dose of RBV for 12 or 24 days. SVR12 was 90% in the 24-week group and 77% in the 12-week group. Patients with cirrhosis had lower SVR12 rates than those without cirrhosis in both arms.
Despite the favourable SVR12 rates at 24 weeks, this combination is suboptimal compared with combinations including two DAAs, which allow shorter duration and show fewer associated side effects, particularly in patients with cirrhosis.

3.3.2 Sofosbuvir plus simeprevir
PLUTO is a multicentre Spanish study including 40 patients with HCV GT4 infection.[33] This single-arm study evaluated the efficacy and safety of a 12-week regimen of SOF 400 mg plus SMV 150 mg daily. All patients achieved SVR12 regardless of their baseline characteristics (18% cirrhosis and 68% treatment-experienced). Adverse events occurred in 50%; all were grade 1 and grade 2. The most common adverse event was headache (20%).

The preliminary efficacy results of the phase-IIa OSIRIS study are in line with those seen in the PLUTO study.[34] OSIRIS is being conducted in Egypt and includes 63 treatment-naïve or experienced patients with and without cirrhosis. All have HCV GT4 infection and are under treatment with SMV 150 mg plus SOF 400 mg daily. High SVR4 rates (95%-100%) have been seen with 12 weeks of treatment regardless of the prior PegIFN plus RBV response or cirrhosis stage. The initial safety data show no discontinuations due to adverse events, and no grade 3 or 4 treatment-related adverse events. The study remains open pending SVR12.

The SOF plus SMV regimen has also been evaluated in the real world. In the French HEPATHER cohort, 34 HCV GT4 patients (82% with compensated cirrhosis and 73% treatment-experienced) were treated with SOF 400 mg plus SMV for 12 or 24 weeks with or without RBV.[35] SVR12 was attained in all patients receiving RBV in their regimen. In a study conducted in the Netherlands, HCV GT4-infected patients were treated with SOF plus SMV (with or without RBV) for 12 weeks. Treatment-naive and treatment-experienced patients were included, and SVR12 was achieved in 49 of 53 patients (92%).[36]

Regarding these results, SOF plus SMV would be a combination option for HCV GT4 infected patients. RBV addition could be considered in treatment-experienced patients.

3.3.3 Sofosbuvir plus daclatasvir
The ATU study investigated a French cohort including 215 patients with HCV GT4 infection and characteristics associated with a low response to treatment, such as moderate liver fibrosis, extrahepatic manifestations, recurrence following liver transplantation and placement on the liver or kidney transplant lists.[37] Among the total, 110 (52%) patients were treated with a 24-week regimen including SOF 400 mg and DCV 30 mg daily, and 63 (30%) patients received the same regimen for 12 weeks. RBV was added in eight patients in the 12-week regimen group and in 31 patients receiving the 24-week regimen. The overall SRV12 rate in HCV GT4 patients was around 91%. SVR12 in patients with cirrhosis (including decompensated cirrhosis) was 90%. The 12-week regimen group showed the highest number of treatment failures. This is a safe regimen with few discontinuations (1%), and the most common adverse event was asthenia in 10% of patients.

4 Treatment of Decompensated Cirrhosis
There are few available studies using the new DAA agents in GT4-infected patients with decompensated cirrhosis. The phase-II SOLAR-I study enrolled GT1- and GT4-infected patients with cirrhosis and moderately or severely impaired liver function, and liver transplant recipients with or without cirrhosis and mild, moderate or severe liver impairment, or fibrosing cholestatic hepatitis.[38] Patients were randomized into two arms to receive 12 or 24 weeks of LDV/SOF plus RBV, respectively. In total, 337 patients were enrolled, and 1% (4/337) had HCV GT4. Overall SVR12 rates in patients with moderate hepatic impairment were 87% in the 12-week regimen and 88% in the 24-week regimen. In liver transplant recipients, SVR12 was lower in those in Child–Turcotte–Pugh class C, with 60% and 75% in the 12- and 24-week regimens, respectively, compared noncirrhotic transplant recipients, with SVR12 rates of 96% and 98%, respectively. Treatment had to be discontinued prematurely in 4% patients because of adverse events. Ten patients died, mainly from complications related to hepatic decompensation. LDV/SOF plus weight-based RBV was associated with high SVR12 rates and good tolerance in decompensated and severe liver impairment, but there were only four GT4 patients in the cohort.

SOLAR-II was a multicentre study that extended data on the LDV/SOF plus RBV regimen in GT4 decompensated cirrhotic patients.[39] In total, 333 patients with advanced liver impairment were enrolled, 37 of whom (11%) were HCV GT4. LDV/SOF plus weight-based RBV were administered in 12- or 24-week regimens. SVR12 rates in GT4 were 78% (14/18) in the group receiving a 12-week regimen and 94% (16/17) in those treated for 24 weeks. The discontinuation rates were similar to those of SOLAR-I. Seventeen patients died due to complications of hepatic decompensation.
The phase-III study, ASTRAL-4, enrolled treatment-naive and treatment-experienced patients with decompensated cirrhosis infected with HCV genotypes 1 (78%), 2 (4%), 3 (15%), 4 (3%) and 6 (<1%).[40] Patients were randomized at a 1:1:1 ratio to receive SOF/VEL once daily for 12 weeks, SOF plus RBV once daily for 12 weeks or SOF/VEL once daily for 24 weeks. Overall SVR12 rates were 83% in patients receiving 12 weeks SOF/VEL (100%, 4/4 in GT4 patients), 94% in those receiving SOF/VEL plus RBV (100%, 2/2 in GT4 patients) and 86% in those with 24 weeks of SOF/VEL (100%, 2/2 in GT4 patients). All GT4-infected patients achieved SVR12. There were no significant differences in SVR rates between the three groups. NS5A RASs were detected in 72 of 255 patients (28%). Of these 72 patients, 64 (89%) achieved SVR12 compared with 169 of 183 patients (92%) without RASs. Serious adverse events were observed in approximately 16%-18% of patients in each group.

Real-life data are scarce in GT4-infected patients with decompensated cirrhosis. Welzel et al.[41] reported on 49 decompensated HCV patients receiving SOF plus DCV with or without RBV. The overall SVR12 was 92% (45/49). Three patients had GT4 infection, and all achieved SVR12. According to the Child–Turcotte–Pugh scoring system for cirrhosis, 15 were classified as B and eight as C. SVR12 rates in these patients were 80% and 88%, respectively. Please note the low representation of genotype 4 in this cohort.
The benefits of this treatment are unclear, particularly in patients with an advanced Child–Turcotte–Pugh score, because viral clearance seems to have little impact on liver impairment or liver complications.

5 HCV/HIV Co-Infected Patients
The efficacy and safety of treatment for HCV GT4 infection in the HIV co-infected population has been evaluated in a few studies.

ION-4 is a multicentre study involving patients co-infected with HIV-1 and HCV genotypes 1 or 4.[42] All patients received an antiretroviral regimen of tenofovir and emtricitabine with efavirenz, rilpivirine or raltegravir. In addition, all received LDV 90 mg plus SOF 400 mg in a single pill once daily for 12 weeks. In total, 335 patients were enrolled, 20% had cirrhosis, and 55% had received prior HCV treatment. SVR12 was achieved in 96% of the total cohort and in all patients (8/8) with GT4 infection. SVR12 rates were similar in the various subgroups regardless of treatment experience or cirrhosis stage. There were no cases of HIV-1 virological rebound, and none of the patients discontinued treatment because of adverse events.

The ALLY-2 study analysed 203 HCV/HIV co-infected patients (three patients had GT4) receiving 12 or 8 weeks of SOF 400 mg plus DCV 60 mg, daily.[43] SVR12 rates were 97% after 12 weeks of treatment and 76% after 8 weeks. All GT4-infected patients achieved SVR12.
A subanalysis by antiretroviral regimen class reported that SVR12 was 97% and was similar across the antiretroviral regimens included.[44] SOF plus DCV is an attractive combination for HCV/HIV co-infected patients, but further data in GT4-infected patients are needed.

The phase-III C-EDGE CO-INFECTION study is a multicentre trial including HIV patients co-infected with HCV genotypes 1, 4 and 6.[45] In total, 218 patients were enrolled and all received GZR/EBR for 12 weeks. The SVR12 rate in patients with GT4 infection was 96% (27/28), with only one relapse, occurring in a noncirrhotic patient. This RBV-free combination achieved a high SVR12 in HCV/HIV co-infected patients without RBV adverse events.

There is little information on GT4 HCV/HIV co-infected patients treated with ombitasvir and paritaprevir regimens. This would likely be an effective, safe combination, as indicated in genotype 1 by the TURQUOISE-I study,[46] but additional data are needed to recommend this combination in this specific population.

6 DAA Failures
6.1 Genotype 4. Resistance-associated substitutions
Only 2% to 5% of HCV GT4 patients fail DAA treatment. Pawlosky et al. reviewed the profiles of patients who experienced treatment failure in each of the major studies using any type of combination therapy. Most of the information came from HCV GT1-infected patients and very little from HCV GT4.

The emergence of HCV RASs is determined by the genetic barrier to the drug, the fitness of the resistant viral population and blood levels of the drug. The dynamics of RASs after discontinuation of DAAs differs depending on the antiviral agent. NS3/4 protease inhibitor RASs disappear within some time after completion of treatment. However, NS5A RASs persist for years and could impact on the selection of retreatment strategies.[47]

RASs to NS5A inhibitors at baseline did not demonstrate a significant impact on SVR12 in combination regimens of SOF/LDV, SOF/VEL or SOF plus DCV, except in treatment-experienced GT1a patients, with or without cirrhosis, in whom lower SVR12 rates were observed. Very limited data are available in GT4 infection. In patients with NS5A RASs failing DAA treatment, the current recommendation is to extend treatment to 24 weeks and add RBV. This is based on the findings from small studies showing a higher SVR12.[48] Although there are no available data in GT4 infection, NS5A inhibitor resistance did not have an impact on SVR12 in GT1 patients receiving an OBV/PTV/R regimen with RBV. Similar results were found for the EBR/GZR combination, with the exception of GT1a patients and treatment-experienced GT1b patients, in whom SVR12 rates were lower. Hence, associated RBV and 16-week or 18-week duration are required in these patients. Again, no resistance data are available in GT4 for this combination. NS3 RASs at baseline do not appear have impact on SVR12.

Presence of the Q80K NS3 resistance substitution does not affect SVR12 in GT4 infection, unlike what occurs in GT1a patients, especially treatment-experienced ones.[49]
Some re-treatment strategies after failing DAAs have been explored in a small number of patients. In a recent study, 15 GT1- and GT4-infected patients who failed a DCV-based regimen (DCV plus PegIFN plus RBV, with or without asunaprevir) received SOF plus SMV without RBV for 12 weeks. Thirteen (87%) achieved SVR12, including all those with GT4 infection.[50] Further data on re-treatment of GT4 patients are needed before a strong recommendation can be established. In the meantime, one re-treatment approach could be a combination of SOF with a DAA of a different class than that previously used plus RBV, and extending therapy to 24 weeks.

7 Summary
In summary, the treatment options for HCV GT4 are now continually growing. The lower SVR rates reported in the past have been eliminated since the development of the new DAA agents. The NS5B-inhibitor, sofosbuvir, has been and remains the cornerstone of the current IFN-free therapies, achieving high SVR12 rates with a good safety profile. Combinations of NS5B inhibitors with NS5A or NS3/4 may be optimal strategies for the treatment of GT4-infected patients with compensated cirrhosis and those previously treated with PegIFN/RBV regimens. Nonetheless, other combinations without NS5B inhibitors, such as NS5A plus NS3/4-inhibitors, have shown SVR rates and safety profiles similar to those of the sofosbuvir combination. Despite the paucity of studies in HCV GT4 infection, some cohorts have provided information of promising SVR12 rates and safety profiles in special populations, such as HCV/HIV co-infected patients and patients with decompensated cirrhosis. These limited data encourage more aggressive use of DAA agents in these populations.
Unfortunately, data on re-treatment strategies for GT4-infected patients who fail IFN-free therapy are nonexistent. We need a greater representation of GT4 patients in real-life studies to provide GT4 infection with a proper identity and remove it from the shadow of GT1.

Maria Buti and Rafael Esteban have received grant for Gilead, MSD, Abbvie and BMS. Mar Riveiro-Barciela has received grant for Gilead. Jordi Llaneras has no personal interests to declare.

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